The decline in muscle mass and quality that occurs with advancing age, termed sarcopenia, can profoundly limit functional abilities, independence, and result in a decreased quality of life. Despite progress that has been made to unravel many of the functional and phenotypic changes that occur in skeletal muscle over the course of the aging process, questions remain regarding the mechanisms that trigger these adaptations. Our long- term goal is to understand factors which lead to the development of sarcopenia that may foster more effective therapeutic interventions to prevent or delay aging-related muscle loss. Our group has recently identified the occurrence of elevated non-heme iron levels in aged skeletal muscle and has suggested a fundamental role of iron accumulation in the progression of sarcopenia. The aging-associated increase in skeletal muscle iron status could be a vital factor leading to the development of oxidative stress and muscle dysfunction. The current experiments will utilize a well-accepted rodent model to delineate the time course of skeletal muscle iron status and regulation changes that occur with aging and to assess the efficacy of iron chelation therapy in the attenuation of aging-associated sarcopenia. Aim #1 is to evaluate the impact of aging on the iron distribution and progression of iron accumulation in skeletal muscle. These experiments will reveal total, non- heme, and heme iron distributions in skeletal muscle over the course of the aging process. Aim #2 is to delineate aging-related alterations in skeletal muscle iron regulation. Elucidation of the temporal response of iron regulation mechanisms will provide necessary insight into the potential factors that lead to iron accumulation. Aim #3 is to ascertain the impact of aging-associated iron accumulation on the development of skeletal muscle oxidative injury, atrophy, and contractile dysfunction. We will utilize prolonged administration of the iron chelator, pyridoxal isonicotinoyl hydrazone (PIH), to determine the relative importance of iron accumulation as a factor involved in the development of sarcopenia. The results of these experiments will provide valuable insight into the putative role of iron in the development of sarcopenia that will provide the necessary information for future RO1 applications with the objective of improving muscle quality and function of elderly individuals. PUBLIC HEALTH RELEVANCE: The decline in muscle quality and function with advancing age, termed sarcopenia, is a significant health- related concern that can limit a person's functional independence and increase the risk of serious injury. The accumulation of iron in muscle may be a significant factor in the development of sarcopenia. This work is relevant to public health in its aims to uncover the relation between muscle iron changes and sarcopenia so that future studies can be implemented with the objective of improving muscle quality and function of elderly individuals.